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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1460-1471.
Prepublished online as a Blood First Edition Paper on October 12, 2006; DOI 10.1182/blood-2006-07-030726.


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HEMATOPOIESIS

The hypomorphic Gata1low mutation alters the proliferation/differentiation potential of the common megakaryocytic-erythroid progenitor

Barbara Ghinassi1,2, Massimo Sanchez3, Fabrizio Martelli1, Giovanni Amabile3, Alessandro Maria Vannucchi4, Giovanni Migliaccio3, Stuart H. Orkin5, and Anna Rita Migliaccio1,6

1 Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore Sanità, Rome, Italy; 2 Department of Biomorphology, University G. D'Annunzio, Chieti, Italy; 3 Department of Cell Biology and Neurosciences, Istituto Superiore Sanità, Rome, Italy; 4 Department of Hematology and Oncology, University of Florence, Italy; 5 Department of Pediatric Oncology, Children's Hospital, Dana Farber Cancer Institute, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA; 6 Department of Medicine and Myeloproliferative Disease–Research Consortium (Pathology), University of Illinois at Chicago

Recent evidence suggests that mutations in the Gata1 gene may alter the proliferation/differentiation potential of hemopoietic progenitors. By single-cell cloning and sequential replating experiments of prospectively isolated progenitor cells, we demonstrate here that the hypomorphic Gata1low mutation increases the proliferation potential of a unique class of progenitor cells, similar in phenotype to adult common erythroid/megakaryocytic progenitors (MEPs), but with the "unique" capacity to generate erythroblasts, megakaryocytes, and mast cells in vitro. Conversely, progenitor cells phenotypically similar to mast cell progenitors (MCPs) are not detectable in the marrow from these mutants. At the single-cell level, about 11% of Gata1low progenitor cells, including MEPs, generate cells that will continue to proliferate in cultures for up to 4 months. In agreement with these results, trilineage (erythroid, megakaryocytic, and mastocytic) cell lines are consistently isolated from bone marrow and spleen cells of Gata1low mice. These results confirm the crucial role played by Gata1 in hematopoietic commitment and identify, as a new target for the Gata1 action, the restriction point at which common myeloid progenitors become either MEPs or MCPs.


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